Kugita et. al., U.S. Pat. No. 3,562,257 (Feb. 9, 1971), discloses benzothiazepine derivatives, among which is (+)-cis-5-[2-(dimethylamino)ethyl]-2,3-dihydro-3-hydroxy-2-(4-methoxypheny l)-1,5-benzothiazepin-4(5H)-one acetate (ester) hydrochloride, i.e., diltiazem hydrochloride Diltiazem hydrochloride is a well-known coronary vasodilator.
The current, known commercial process for preparing diltiazem hydrochloride involves the following two steps: (1) hydrolysis of an ester, e.g., the methyl ester, to form the corresponding free propionic acid, and then (2) heating of the free propionic acid in xylenes to cyclize it into 1,5-benzothiazepine, which is further processed into diltiazem and then its hydrochloride. See generally, Igarashi et. al., U.S. Pat. No. 4,552,695 (Nov. 12, 1985), e.g., at column 7, lines 10-47.
Known prior art has shown attempts to cyclize the ester, e.g., the methyl ester, directly into the 3-(hydroxy)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepine. Also, direct cyclization attempts have been generally disclosed in the preparation of an 8-chloro analog of diltiazem. However, yields are generally low.
For example, Kugita et. al., Chem. Pharm. Bull., 18(10), 2028-2037 (1970), reports on synthesis of 1,5-benzothiazepine derivatives, to include at page 2032 thereof, where it is reported that cyclization of the amino ester into the 1,5-benzothiazepine was effected by heating the ester with sulfuric acid or with acetic acid, but that hydrolysis of the amino ester to the amino carboxylic acid and cyclization of the amino acid in boiling xylene gave more satisfactory yield of the cyclic amide.
And, Takeda et. al., U.S. Pat. No. 4,567,175 (Jan. 28, 1986), discloses 8-chloro-1,5-benzothiazepine derivatives, to include cyclization attempts of esters such as is illustrated at columns 5-7 and described at column 7, lines 54-56, and at from column 8, line 65, to column 9, line 8. Cyclizations of the acid compounds are also illustrated and described therein.
Basu et. al., Synth. Commun., 19(3 & 4), 627-631 (1989), reports on a mild and selective method of ester hydrolysis. This method employs Dowex-50 resin.
What is lacking and needed in the art is a more efficient way to prepare such a benzothiazepine as diltiazem hydrochloride, and so forth, particularly on a commercial scale. Desirably, any solution to such a problem perhaps would also be able to be applied in preparations of other organic compounds, and other problems also might be solved as well.